Movements of cells include contraction, migration, release, aggregation and the like, and phosphorylation of the myosin regulatory light chain is important for these cell movements. The myosin regulatory light chain is a subunit having a molecular weight of 20 kDa and constituting myosin, which exists in smooth muscle cells and various non-muscle cells such as neutrophils, platelets and nerve cells of warm-blooded animals (Barany, K., et al., Biochemistry of Smooth Muscle Contraction, pp. 21-35, 1996). Myosin existing in smooth muscle cells and various non-muscle cells such as neutrophils, platelets and nerve cells of warm-blooded animals is constituted by a myosin heavy chain subunit having a molecular weight of about 200 kDa, the myosin regulatory light chain subunit having a molecular weight of about 20 kDa, and a myosin constitutive light chain subunit having a molecular weight of about 17 kDa.
The myosin regulatory light chain is mainly phosphorylated by the myosin light chain kinase to increase the activity of myosin ATPase existing in the myosin heavy chain subunit (Barany, M., et al., Biochemistry of Smooth Muscle Contraction, pp. 321-339, 1996). It is known that the activated myosin having the increased ATPase activity becomes possible to interact with actin and activates movement apparatuses of cytoskeleton to activate cell movements. More specifically, it is known that activation of myosin relates to cell contraction (Kamm, K., et al., Annu. Rev. Physiol., 51, pp. 299-313, 1989). It is also known that activation of myosin relates to change of cell morphology (Schmidt, J. T. et al., J, Neurobiol., 52 (3), pp. 175-188, 2002). It is known that activation of myosin relates to cell migration (Niggli, V., FEBS Lett., 445, pp. 69-72, 1999). Further, it is known that activation of myosin relates to cell release (Kitani, S., et al., Biochem. Biophys. Res. Commun., 183, pp. 48-54, 1992). It is further known that activation of myosin relates to cell aggregation (Itoh, K., et al., Biochim. Biophys. Acta., 1136, pp. 52-56, 1992). It is also known that activation of myosin relates to cell apoptosis (Mills, J. C. et al., J. Cell Biol., Vol. 140, No. 3, pp. 627-636, 1998). Based on these findings, it is considered that an agent which inhibits the phosphorylation of the myosin regulatory light chain suppresses cell contraction, regulates change of cell morphology, suppresses cell migration, suppresses cell release, suppresses cell aggregation and suppresses cell apoptosis.
Cell contraction is deeply involved in diseases relating to contraction of various smooth muscle layers. Examples of such diseases include, for example, hypertension (Samlyo, A. P., et al., Rev. Physiol. Biochem. Pharmacol., Vol. 134, pp. 209-34, 1999), angina pectoris (Shimokawa et al., Cardiovasc. Res., Vol. 43, No. 4, pp. 1029-39, 1999; Satoh, H., et al., Jpn. J. Pharmacol., 79 (suppl.), p. 211, 1999), cerebral vascular spasm (M. Satoh et al., the 57th General Meeting of Japan Neurosurgical Society, Collection of Abstracts, 153, 1998; N. Ono et al., Pharmacol. Ther., Vol. 82, No. 2-3, pp. 123-31, 1991; Shimokawa et al., Cardiovasc. Res., Vol. 43, No. 4, pp. 1029-39, 1999), erectile dysfunction (Andersson, K E. et al., World J. Vrol., 15, pp. 14-20, 1997), bronchial asthma (K. Iidzuka, Allergy, 47, 943, 1998; K. Iidzuka et al., Jpn. J. Respirology Society, 37, 196, 1999) and the like.
Change of cell morphology is deeply involved in diseases relating to morphological change of various cells. Examples of the diseases relating to change of cell morphology include, for example, as those relating to nerve cells of eyes, various nerve dysfunctions such as diabetic retinopathy, and glaucoma (Arakawa, Y., et al., BIO Clinica, 17 (13), pp. 26-28, 2002). Further, cell migration is deeply involved in diseases relating to migration of various cells. Examples of such diseases include, for example, cancer invasion and metastasis (Itoh, K. et al., Nat. Med., Vol. 5, No. 2, pp. 221-5, 1999; Keely, P. et al., Trends Cell Biol., Vol. 8, No. 3, pp. 101-6, 1998), nephritis (Fujimoto, O. et al., Journal of Japanese Society of Internal Medicine, 88 (1), pp. 148-58, 1998) and the like.
Furthermore, it is considered that cell release is deeply involved in various allergies and the like (Keane-Myers A. et al., Curr. Allergy Asthma Rep., 1(6):550-557, 2001), and further, cell aggregation is considered to be deeply involved in thrombosis and the like (Nakai, K. et al., Blood, Vol. 90, No. 10, pp. 3736-42, 1997). Further, it is known that cell apoptosis is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and glaucoma, viral diseases, hepatic diseases and the like (Thompson, C. B., Science, Vol. 267, pp. 1456-1462, 1995).
As pathways for regulating phosphorylation of myosin regulatory light chain, two pathways are known, i.e., a pathway based on activation of myosin regulatory light chain kinase induced by elevation of intracellular calcium level, and a pathway based on inactivation of myosin dephosphorylation enzyme resulting from phosphorylation of the enzyme induced by activation of Rho kinase due to activation of low-molecular-weight Rho protein (Fukata, Y., et al., Trends Pharmacol. Sci., 22, pp. 32-39, 2001).
More specifically, it is considered that compounds which inhibit Rho kinase suppress cell contraction, regulate change of cell morphology, suppress cell migration, suppress cell release, suppress cell aggregation, and suppress cell apoptosis, like medicaments which inhibit phosphorylation of myosin regulatory light chain.
Based on these findings, it is considered that a substance which inhibits Rho kinase is useful as an active ingredient of a medicament for prophylactic and/or therapeutic treatment of a disease relating to cell contraction, disease relating to change of cell morphology, disease relating to cell migration, disease relating to cell release, disease relating to cell aggregation, and/or disease relating to cell apoptosis.
As agents inhibiting the phosphorylation of myosin regulatory light chain, isoquinoline derivatives are known. For example, it has been reported that 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) inhibits the phosphorylation of myosin regulatory light chain of mesenteric artery (Suzuki, A. et al., Br. J. Pharmacol., 109, pp. 703-712, 1993), and there are also known drugs inhibiting the phosphorylation of myosin regulatory light chain of iris smooth muscle (Howe, P. H. et al., Biochem J., 255, pp. 423-429, 1988), and astrocyte (Mobley P. L., et al., Exp. Cell Res., 214, pp. 55-66, 1994). Further, 5-substituted isoquinoline derivatives are also known (International Patent Publication No. 2004/009555). However, the N atom of sulfonamide in these 5-substituted isoquinoline derivatives does not form a ring, and thus they have a structure different from that of the compounds of the present invention. Further, tricyclic compounds are also known (International Patent Publication No. 2004/108724). However, these compounds are tricyclic compounds and do not have sulfonamide, and therefore they are structurally different from the compounds of the present invention.
Further, known Rho kinase inhibitors also include the amide derivatives disclosed in International Patent Publication WO98/06433; isoquinolinesulfonyl derivatives disclosed in International Patent Publication WO97/23222, Uehata, M. et al., Nature, 389, pp 990-994, 1997, and International Patent Publication WO99/64011; heterocyclic amino derivatives disclosed in International Patent Publication WO01/56988; indazole derivatives disclosed in International Patent Publication WO02/100833; quinazoline derivatives disclosed in International Patent Publications WO02/076976 and WO02/076977, and the like. However, any of these compounds are structurally different from the compounds of the present invention.